Transfer of the six "internal" genes of the avian influenza A/Mallard/78 virus to four human influenza A viruses (one H1N1 strain and three H3N2 strains) reproducibly attenuated the resulting reassortants for monkeys or hamsters. Avian influenza NP and M genes singly or RNA 1 and NS genes in combination play a role in attenuation of these reassortants for monkeys. Transfer of the six "internal" genes of the avian A/Pintail/119/79 influenza virus to the human influenza A/WAshington/80 (H3N2) virus also attenuated the resulting reassortant for monkeys. The A/Washington/80 X A/ Pintail/79 reassortant was satisfactorily attenuated, not tansmissible, immunogenic, and safe in monkeys. Immunogenicity was demonstrated by the induction of resistance to challenge with wild type virulent human influenza virus. These studies form the basis for evaluation of these promising reassortant viruses in humans.